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Published on: March 23, 2011
TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice
Teng Jiang1,2, Yu Wan3, Ying-Dong Zhang4
1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. jt870918@163.com.
Abstract:
Previously, we showed that overexpression of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific immune receptor, in the brain of a middle-aged (7 months old) APPswe/PS1dE9 mice could ameliorate Alzheimer's disease (AD)-related neuropathology by enhancement of microglial amyloid-β (Aβ) phagocytosis. Since AD is an age-related neurodegenerative disorder, it is critical to assess the efficacy of TREM2 overexpression in aging animals with an advanced disease stage. In vivo, we employed a lentiviral strategy to overexpress TREM2 in the brain of aging (18 months old) APPswe/PS1dE9 mice, and observed its efficacy on AD-related neuropathology and cognitive functions. Afterwards, we directly isolated microglia from middle-aged and aging APPswe/PS1dE9 mice and determined effects of TREM2 overexpression on microglial Aβ phagocytosis and Aβ-binding receptors expression in vitro. In aging APPswe/PS1dE9 mice, TREM2 overexpression has no beneficial effect on AD-related neuropathology and spatial cognitive functions. Of note, in vitro experiments showed a significant reduction of Aβ phagocytosis in microglia from aging APPswe/PS1dE9 mice, possibly attributing to the declined expression of Aβ-binding receptors. Meanwhile, this phagocytic deficit in microglia from aging APPswe/PS1dE9 mice cannot be rescued by TREM2 overexpression. Taken together, our study shows that TREM2 overexpression fails to provide neuroprotection in aging APPswe/PS1dE9 mice, possibly attributing to deficits in microglial Aβ phagocytosis at the late-stage of disease progression. These findings indicate that TREM2-mediated protection in AD is at least partially dependent on the reservation of microglial phagocytic functions, emphasizing the importance of early therapeutic interventions for this devastating disease.
Insights
Overexpressing triggering receptor expressed on myeloid cells 2 (TREM2) in aging Alzheimer's mice did not improve neuropathology or cognition. This suggests TREM2 therapy effectiveness depends on early intervention before microglial phagocytosis declines.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) is an age-related neurodegenerative disorder.
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor implicated in AD pathogenesis.
- Previous studies showed TREM2 overexpression ameliorated AD pathology in middle-aged mice.
Purpose of the Study:
- To evaluate the efficacy of TREM2 overexpression in aging APPswe/PS1dE9 mice with advanced AD neuropathology.
- To investigate the impact of TREM2 on microglial amyloid-beta (Aβ) phagocytosis and cognitive functions in aged AD models.
- To determine if TREM2 overexpression can rescue phagocytic deficits in aged microglia.
Main Methods:
- Lentiviral strategy to overexpress TREM2 in the brains of aging (18-month-old) APPswe/PS1dE9 mice.
- Assessment of AD-related neuropathology and spatial cognitive functions in vivo.
- In vitro isolation and analysis of microglia from middle-aged and aging APPswe/PS1dE9 mice to determine Aβ phagocytosis and Aβ-binding receptor expression.
Main Results:
- TREM2 overexpression showed no beneficial effects on neuropathology or cognitive functions in aging APPswe/PS1dE9 mice.
- In vitro, microglia from aging mice exhibited reduced Aβ phagocytosis, linked to decreased Aβ-binding receptor expression.
- TREM2 overexpression failed to rescue the phagocytic deficit in microglia from aging APPswe/PS1dE9 mice.
Conclusions:
- TREM2 overexpression is ineffective in providing neuroprotection in aged AD mouse models with advanced disease.
- The diminished microglial phagocytic capacity in late-stage AD may underlie the lack of TREM2 therapeutic benefit.
- These findings highlight that TREM2-mediated neuroprotection is contingent on preserved microglial function, underscoring the need for early therapeutic intervention in AD.
